Db. Hardy et al., Prostaglandins and leukotriene B-4 are potent inhibitors of 11 beta-hydroxysteroid dehydrogenase type 2 activity in human choriocarcinoma JEG-3 cells, BIOL REPROD, 61(1), 1999, pp. 40-45
The 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) is responsib
le for the inactivation of glucocorticoids. This is the predominant isozyme
in the human placenta, where it is proposed to protect the fetus from high
levels of maternal cortisol. In the present study, we examined the effects
of eicosanoids on the activity of 11 beta-HSD2 in human choriocarcinoma JE
G-3 cells, a well-established model for placental trophoblasts. Treat ment
of JEG-3 cells for 24 h with either prostaglandin (PG) E-2 or F-2 alpha att
enuated 11 beta-HSD2 activity (similar to 40%). Paradoxically, indomethacin
, an inhibitor of cyclooxygenases, inhibited (similar to 40%) rather than s
timulated the activity of this enzyme. This indicated that the arachidonic
acid metabolism may be diverted to other pathway(s), the products of which
may inhibit 11 beta-HSD2 activity. To determine whether the lipoxygenase pa
thways were involved, the cells were treated with nordihydroguaretic acid (
NDGA), a blocker of all three (5-, 12-, and 15-) lipoxygenases. NDGA caused
a 3-fold increase in 11 beta-HSD2 activity, To further delineate which spe
cific lipoxygenase pathway was involved, the cells were incubated with zile
uton, a selective inhibitor of 5-lipoxygenase, This resulted in a similar i
ncrease in 11 beta-HSD2 activity, suggesting that the products of this path
way (e.g., leukotrienes) may be involved. Given that leukotriene B-4 (LTB4)
is the most biologically active product of the 5-lipoxygenase pathway,we t
reated the cells with LTB4, which inhibited 11 beta-HSD2 activity in a time
- and dose-dependent manner with a maximal effect (60% reduction) at 10 nM
for 9 h. Semiquantitative reverse transcription-polymerase chain reaction a
nalysis revealed that 11 beta-HSD2 mRNA levels were not altered by the addi
tion of LTB4, PGE(2), or PGF(2 alpha), indicating an effect at the posttran
scriptional level. In conclusion, these results demonstrate that prostaglan
dins and LTB4 are potent inhibitors of 11 beta-HSD2 activity in JEG-3 cells
, suggesting that placental 11 beta-HSD2 activity is modulated by these loc
ally produced eicosanoids. This is the first time that the products of arac
hidonic acid metabolism have been found to regulate the activity of 11 beta
-HSD2.